Imidazopyridine inhibitors of IAP

ABSTRACT

The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula I: wherein Q, X 1 , X 2 , Y, Z R 1 , R 2 , R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 6 , R 6 ′ and n are as described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S. Ser.No. 60/870,821, filed Dec. 19, 2006, which is incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors of IAPproteins useful for treating cancers.

BACKGROUND OF THE INVENTION

Apoptosis or programmed cell death is a genetically and biochemicallyregulated mechanism that plays an important role in development andhomeostasis in invertebrates as well as vertebrates. Aberrancies inapoptosis that lead to premature cell death have been linked to avariety of developmental disorders. Deficiencies in apoptosis thatresult in the lack of cell death have been linked to cancer and chronicviral infections (Thompson et al., (1995) Science 267, 1456-1462).

One of the key effector molecules in apoptosis are the caspases(cysteine containing aspartate specific proteases). Caspases are strongproteases, cleaving after aspartic acid residues and once activated,digest vital cell proteins from within the cell. Since caspases are suchstrong proteases, tight control of this family of proteins is necessaryto prevent premature cell death. In general, caspases are synthesized aslargely inactive zymogens that require proteolytic processing in orderto be active. This proteolytic processing is only one of the ways inwhich caspases are regulated. The second mechanism is through a familyof proteins that bind and inhibit caspases.

A family of molecules that inhibit caspases are the Inhibitors ofApoptosis (IAP) (Deveraux et al., J Clin Immunol (1999), 19:388-398).IAPs were originally discovered in baculovirus by their functionalability to substitute for P35 protein, an anti-apoptotic gene (Crook etal. (1993) J Virology 67, 2168-2174). IAPs have been described inorganisms ranging from Drosophila to human. Regardless of their origin,structurally, IAPs comprise one to three Baculovirus IAP repeat (BIR)domains, and most of them also possess a carboxyl-terminal RING fingermotif. The BIR domain itself is a zinc binding domain of about 70residues comprising 4 alpha-helices and 3 beta strands, with cysteineand histidine residues that coordinate the zinc ion (Hinds et al.,(1999) Nat. Struct. Biol. 6, 648-651). It is the BIR domain that isbelieved to cause the anti-apoptotic effect by inhibiting the caspasesand thus inhibiting apoptosis. As an example, human X-chromosome linkedIAP (XIAP) inhibits caspase 3, caspase 7 and the Apaf-1-cytochrome Cmediated activation of caspase 9 (Deveraux et al., (1998) EMBO J. 17,2215-2223). Caspases 3 and 7 are inhibited by the BIR2 domain of XIAP,while the BIR3 domain of XIAP is responsible for the inhibition ofcaspase 9 activity. XIAP is expressed ubiquitously in most adult andfetal tissues (Liston et al, Nature, 1996, 379(6563):349), and isoverexpressed in a number of tumor cell lines of the NCI 60 cell linepanel (Fong et al, Genomics, 2000, 70:113; Tamm et al, Clin. Cancer Res.2000, 6(5):1796). Overexpression of XIAP in tumor cells has beendemonstrated to confer protection against a variety of pro-apoptoticstimuli and promotes resistance to chemotherapy (LaCasse et al,Oncogene, 1998, 17(25):3247). Consistent with this, a strong correlationbetween XIAP protein levels and survival has been demonstrated forpatients with acute myelogenous leukemia (Tamm et al, supra).Down-regulation of XIAP expression by antisense oligonucleotides hasbeen shown to sensitize tumor cells to death induced by a wide range ofpro-apoptotic agents, both in vitro and in vivo (Sasaki et al, CancerRes., 2000, 60(20):5659; Lin et al, Biochem J., 2001, 353:299; Hu et al,Clin. Cancer Res., 2003, 9(7):2826). Smac/DIABLO-derived peptides havealso been demonstrated to sensitize a number of different tumor celllines to apoptosis induced by a variety of pro-apoptotic drugs (Arnt etal, J. Biol. Chem., 2002, 277(46):44236; Fulda et al, Nature Med., 2002,8(8):808; Guo et al, Blood, 2002, 99(9):3419; Vucic et al, J. Biol.Chem., 2002, 277(14):12275; Yang et al, Cancer Res., 2003, 63(4):831).

Melanoma IAP (ML-IAP) is an IAP not detectable in most normal adulttissues but is strongly upregulated in melanoma (Vucic et al., (2000)Current Bio 10:1359-1366). Determination of protein structuredemonstrated significant homology of the ML-IAP BIR and RING fingerdomains to corresponding domains present in human XIAP, C-IAP1 andC-IAP2. The BIR domain of ML-IAP appears to have the most similaritiesto the BIR2 and BIR3 of XIAP, C-IAP1 and C-IAP2, and appears to beresponsible for the inhibition of apoptosis, as determined by deletionalanalysis. Furthermore, Vucic et al., demonstrated that ML-IAP couldinhibit chemotherapeutic agent induced apoptosis. Agents such asadriamycin and 4-tertiary butylphenol (4-TBP) were tested in a cellculture system of melanomas overexpressing ML-IAP and thechemotherapeutic agents were significantly less effective in killing thecells when compared to a normal melanocyte control. The mechanism bywhich ML-IAP produces an anti-apoptotic activity is in part throughinhibition of caspase 3 and 9. ML-IAP did not effectively inhibitcaspases 1, 2, 6, or 8.

Since apoptosis is a strictly controlled pathway with multipleinteracting factors, the discovery that IAPs themselves are regulatedwas not unusual. In the fruit fly Drosophila, the Reaper (rpr), HeadInvolution Defective (hid) and GRIM proteins physically interact withand inhibit the anti-apoptotic activity of the Drosophila family ofIAPs. In the mammal, the proteins SMAC/DIABLO act to block the IAPs andallow apoptosis to proceed. It was shown that during normal apoptosis,SMAC is processed into an active form and is released from themitochondria into the cytoplasm where it physically binds to IAPs andprevents the IAP from binding to a caspase. This inhibition of the IAPallows the caspase to remain active and thus proceed with apoptosis.Interestingly, sequence homology between the IAP inhibitors shows thatthere is a four amino acid motif in the N-terminus of the processed,active proteins. This tetrapeptide appears to bind into a hydrophobicpocket in the BIR domain and disrupts the BIR domain binding to caspases(Chai et al., (2000) Nature 406:855-862, Liu et al., (2000) Nature408:1004-1008, Wu et al., (2000) Nature 408 1008-1012).

SUMMARY OF THE INVENTION

In one aspect of the present invention there is provided novelinhibitors of IAP proteins having the general formula (I)

wherein

-   X₁ and X₂ are each independently O or S;-   Y is a bond, (CR₇R₇)_(m), or S;-   Z is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a    carbocycle or a heterocycle; wherein said alkyl, carbocycle and    heterocycle is optionally substituted with one or more hydroxyl,    alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally    substituted alkyl, amino, cyano, nitro, amidino, guanidino an    optionally substituted carbocycle or an optionally substituted    heterocycle; and wherein one or more CH₂ or CH groups of an alkyl is    optionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—, —C(O)—,    —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—,    —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)—;-   Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a    carbocycle or a heterocycle; wherein said alkyl, carbocycle and    heterocycle is optionally substituted with one or more hydroxyl,    alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally    substituted alkyl, amino, cyano, nitro, amidino, guanidino an    optionally substituted carbocycle or an optionally substituted    heterocycle; and wherein one or more CH₂ or CH groups of an alkyl is    optionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—, —C(O)—,    —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—,    —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)—;-   R₁ is H, OH or alkyl; or R₁ and R₂ together form a 5-8 member    heterocycle;-   R₂ is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle or    heterocyclylalkyl each optionally substituted with halogen,    hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, acyl,    alkoxy, alkylthio, sulfonyl, amino and nitro, wherein said alkyl,    acyl, alkoxy, alkylthio and sulfonyl are optionally substituted with    hydroxy, mercapto, halogen, amino, alkoxy, hydroxyalkoxy and    alkoxyalkoxy;-   R₃ is H or alkyl optionally substituted with halogen or hydroxyl; or    R₃ and R₄ together form a 3-6 heterocycle;-   R₃′ is H, or R₃ and R₃′ together form a 3-6 carbocycle;-   R₄ and R₄′ are independently H, hydroxyl, amino, alkyl, carbocycle,    carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl,    heterocycle, heterocycloalkyl, heterocycloalkyloxy or    heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl,    carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle,    heterocycloalkyl, heterocycloalkyloxy and    heterocycloalkyloxycarbonyl is optionally substituted with halogen,    hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino and nitro;    or R₄ and R₄′ together form a heterocycle;-   R₅ is H or alkyl;-   R₆, and R₆′ are each independently H, alkyl, aryl or aralkyl;-   R₇ is H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl,    amidino, guanidino, alkyl, a carbocycle, a heterocycle or —U—V;    wherein U is —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—,    —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—,    —NR₈—C(NH)—, —C(O)—O— or —O—C(O)— and V is alkyl, a carbocycle or a    heterocycle; and wherein one or more CH₂ or CH groups of an alkyl is    optionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—,    —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—,    —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle and heterocycle is    optionally substituted with hydroxyl, alkoxy, acyl, halogen,    mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano    nitro, amidino, guanidino an optionally substituted carbocycle or an    optionally substituted heterocycle;-   R₈ is H, alkyl, a carbocycle or a heterocycle wherein one or more    CH₂ or CH groups of said alkyl is optionally replaced with —O—, —S—,    —S(O)—, S(O)₂, —N(R₈), or —C(O)—; and said alkyl, carbocycle and    heterocycle is optionally substituted with hydroxyl, alkoxy, acyl,    halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl,    amino, cyano nitro, amidino, guanidino an optionally substituted    carbocycle or an optionally substituted heterocycle; and-   m is 0 to 4.

In another aspect of the invention, there are provided compositionscomprising compounds of formula I and a carrier, diluent or excipient.

In another aspect of the invention, there is provided a method ofinducing apoptosis in a cell comprising introducing into said cell acompound of formula I.

In another aspect of the invention, there is provided a method ofsensitizing a cell to an apoptotic signal comprising introducing intosaid cell a compound of formula I.

In another aspect of the invention, there is provided a method forinhibiting the binding of an IAP protein to a caspase protein comprisingcontacting said IAP protein with a compound of formula I.

In another aspect of the invention, there is provided a method fortreating a disease or condition associated with the overexpression of anIAP protein in a mammal, comprising administering to said mammal aneffective amount of a compound of formula I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

“Acyl” means a carbonyl containing substituent represented by theformula —C(O)—R in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), andheteroaroyl.

“Alkyl” means a branched or unbranched, saturated or unsaturated (i.e.alkenyl, alkynyl) aliphatic hydrocarbon group, having up to 12 carbonatoms unless otherwise specified. When used as part of another term, forexample “alkylamino”, the alkyl portion may be a saturated hydrocarbonchain, however also includes unsaturated hydrocarbon carbon chains suchas “alkenylamino” and “alkynylamino. Examples of particular alkyl groupsare methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl,and the like. The terms “lower alkyl” “C₁-C₄ alkyl” and “alkyl of 1 to 4carbon atoms” are synonymous and used interchangeably to mean methyl,ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or t-butyl.Unless specified, substituted, alkyl groups may contain one, for exampletwo, three or four substituents which may be the same or different.Examples of substituents are, unless otherwise defined, halogen, amino,hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano,amidino, guanidino, urea, sulfonyl, sulfinyl, aminosulfonyl,alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, acylamino, alkoxy,acyl, acyloxy, a carbocycle, a heterocycle. Examples of the abovesubstituted alkyl groups include, but are not limited to; cyanomethyl,nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl,aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl,alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl,methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl,2,4-dichloro(n-butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and thelike. The alkyl group may also be substituted with a carbocycle group.Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,and cyclohexylmethyl groups, as well as the corresponding -ethyl,-propyl, -butyl, -pentyl, -hexyl groups, etc. Substituted alkyls includesubstituted methyls e.g. a methyl group substituted by the samesubstituents as the “substituted C_(n)-C_(m), alkyl” group. Examples ofthe substituted methyl group include groups such as hydroxymethyl,protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl),acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl,carboxymethyl, bromomethyl and iodomethyl.

“Amidine” means the group —C(NH)—NHR in which R is H, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. A particular amidine is the group—NH—C(NH)—NH₂.

“Amino” means primary (i.e. —NH₂), secondary (i.e. —NRH) and tertiary(i.e. —NRR) amines in which R is H, alkyl, a carbocycle, a heterocycle,carbocycle-substituted alkyl or heterocycle-substituted alkyl whereinthe alkyl, alkoxy, carbocycle and heterocycle are as defined herein.Particular secondary and tertiary amines are alkylamine, dialkylamine,arylamine, diarylamine, aralkylamine and diaralkylamine wherein thealkyl is as herein defined and optionally substituted. Particularsecondary and tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine,dipropylamine and disopropylamine.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, imines, as well as many N-heteroatom derivatives which canbe removed to regenerate the desired amine group. Particular aminoprotecting groups are Boc, Fmoc and Cbz. Further examples of thesegroups are found in T. W. Greene and P. G. M. Wuts, “Protective Groupsin Organic Synthesis”, 2^(nd) ed., John Wiley & Sons, Inc., New York,N.Y., 1991, chapter 7; E. Haslam, “Protective Groups in OrganicChemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973,Chapter 5, and T. W. Greene, “Protective Groups in Organic Synthesis”,John Wiley and Sons, New York, N.Y., 1981. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Aryl” when used alone or as part of another term means a carbocyclicaromatic group whether or not fused having the number of carbon atomsdesignated or if no number is designated, up to 14 carbon atoms.Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl,naphthacenyl, and the like (see e.g. Lang's Handbook of Chemistry (Dean,J. A., ed) 13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl.Substituted phenyl or substituted aryl means a phenyl group or arylgroup substituted with one, two, three, four or five, for example 1-2,1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen(F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (forexample C₁-C₆ alkyl), alkoxy (for example C₁-C₆ alkoxy), benzyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, aminomethyl, protectedaminomethyl, trifluoromethyl, alkylsulfonylamino,alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl,heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl,aryl, or other groups specified. One or more methyne (CH) and/ormethylene (CH₂) groups in these substituents may in turn be substitutedwith a similar group as those denoted above. Examples of the term“substituted phenyl” includes but is not limited to a mono- ordi(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl,4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like;a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl,3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; acyanophenyl group, for example, 4-cyanophenyl; a mono- or di(loweralkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl,2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyland the like; a mono or di(alkoxy)phenyl group, for example,3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl,4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl andthe like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or(protected carboxy)phenyl group such 4-carboxyphenyl; a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenylgroups where the substituents are different, for example3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Particularsubstituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl,2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl,4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl,3-methoxy-4-benzyloxyphenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl,3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenylgroups. Fused aryl rings may also be substituted with any, for example1, 2 or 3, of the substituents specified herein in the same manner assubstituted alkyl groups.

“Carbocyclyl”, “carbocyclylic”, “carbocycle” and “carbocyclo” alone andwhen used as a moiety in a complex group such as a carbocycloalkylgroup, refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to14 carbon atoms, for example 3 to 7 carbon atoms, which may be saturatedor unsaturated, aromatic or non-aromatic. Particular saturatedcarbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl groups. A particular saturated carbocycle is cyclopropyl.Another particular saturated carbocycle is cyclohexyl. Particularunsaturated carbocycles are aromatic e.g. aryl groups as previouslydefined, for example phenyl. The terms “substituted carbocyclyl”,“carbocycle” and “carbocyclo” mean these groups substituted by the samesubstituents as the “substituted alkyl” group.

“Carboxy-protecting group” as used herein refers to one of the esterderivatives of the carboxylic acid group commonly employed to block orprotect the carboxylic acid group while reactions are carried out onother functional groups on the compound. Examples of such carboxylicacid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl,benzhydryl, 4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl,alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl,4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl,trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The speciesof carboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the condition of subsequentreaction(s) on other positions of the molecule and can be removed at theappropriate point without disrupting the remainder of the molecule. Inparticular, it is important not to subject a carboxy-protected moleculeto strong nucleophilic bases, such as lithium hydroxide or NaOH, orreductive conditions employing highly activated metal hydrides such asLiAlH₄. (Such harsh removal conditions are also to be avoided whenremoving amino-protecting groups and hydroxy-protecting groups,discussed below.) Particular carboxylic acid protecting groups are thealkyl (e.g. methyl, ethyl, t-butyl), allyl, benzyl and p-nitrobenzylgroups. Similar carboxy-protecting groups used in the cephalosporin,penicillin and peptide arts can also be used to protect a carboxy groupsubstituents. Further examples of these groups are found in T. W. Greeneand P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2^(nd) ed.,John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam,“Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed., PlenumPress, New York, N.Y., 1973, Chapter 5, and T. W. Greene, “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981,Chapter 5. The term “protected carboxy” refers to a carboxy groupsubstituted with one of the above carboxy-protecting groups.

“Guanidine” means the group —NH—C(NH)—NHR in which R is H, alkyl, acarbocycle, a heterocycle, carbocycle-substituted alkyl orheterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle andheterocycle are as defined herein. A particular guanidine is the group—NH—C(NH)—NH₂.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g. TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 2^(nd) ed., John Wiley & Sons, Inc., New York, N.Y.,1991, chapters 2-3; E. Haslam, “Protective Groups in Organic Chemistry”,J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, andT. W. Greene, “Protective Groups in Organic Synthesis”, John Wiley andSons, New York, N.Y., 1981. The term “protected hydroxy” refers to ahydroxy group substituted with one of the above hydroxy-protectinggroups.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or“heterocyclo” alone and when used as a moiety in a complex group such asa heterocycloalkyl group, are used interchangeably and refer to anymono-, bi-, or tricyclic, saturated or unsaturated, aromatic(heteroaryl) or non-aromatic ring having the number of atoms designated,generally from 5 to about 14 ring atoms, where the ring atoms are carbonand at least one heteroatom (nitrogen, sulfur or oxygen), for example 1to 4 heteroatoms. Typically, a 5-membered ring has 0 to 2 double bondsand 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen orsulfur heteroatoms may optionally be oxidized (e.g. SO, SO₂), and anynitrogen heteroatom may optionally be quaternized. Particularnon-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl,oxiranyl, oxetanyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2H-pyranyl,tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl,aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperazinyl andpiperidinyl. A “heterocycloalkyl” group is a heterocycle group asdefined above covalently bonded to an alkyl group as defined above.Particular 5-membered heterocycles containing a sulfur or oxygen atomand one to three nitrogen atoms are thiazolyl, in particularthiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for exampleoxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and1,2,4-oxadiazol-5-yl. Particular 5-membered ring heterocycles containing2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl;triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl,1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Particularbenzo-fused 5-membered heterocycles are benzoxazol-2-yl,benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-memberedheterocycles contain one to three nitrogen atoms and optionally a sulfuror oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, andpyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl,such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, inparticular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides andpyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,pyridazinyl and the 1,3,4-triazin-2-yl groups, are a particular group.Substituents for “optionally substituted heterocycles”, and furtherexamples of the 5- and 6-membered ring systems discussed above can befound in W. Druckheimer et al., U.S. Pat. No. 4,278,793. In a particularembodiment, such optionally substittuted heterocycle groups aresubstituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo,carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino andguanidino.

“Heteroaryl” alone and when used as a moiety in a complex group such asa heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromaticring system having the number of atoms designated where at least onering is a 5-, 6- or 7-membered ring containing from one to fourheteroatoms selected from the group nitrogen, oxygen, and sulfur, and ina particular embodiment at least one heteroatom is nitrogen (Lang'sHandbook of Chemistry, supra). Included in the definition are anybicyclic groups where any of the above heteroaryl rings are fused to abenzene ring. Particular heteroaryls incorporate a nitrogen or oxygenheteroatom. The following ring systems are examples of the heteroaryl(whether substituted or unsubstituted) groups denoted by the term“heteroaryl”: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl andpurinyl, as well as benzo-fused derivatives, for example benzoxazolyl,benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl,benzoimidazolyl and indolyl. A particular “heteroaryl” is:1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl,2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-ylsodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl,2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl,2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 2-methyl-1H-tetrazol-5-yl,1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl,2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-ylN-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl,1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-as-triazin-3-yl,2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl,2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl and8-aminotetrazolo[1,5-b]-pyridazin-6-yl. An alternative group of“heteroaryl” includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl,4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt,1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl,1-methyl-1H-tetrazol-5-yl,1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl,1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-ylsodium salt, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonicacid)-1H-tetrazol-5-yl sodium salt, 1,2,3-triazol-5-yl,1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl,1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt,2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl,tetrazolo[1,5-b]pyridazin-6-yl, and8-aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionallysubstituted as described for heterocycles.

“Inhibitor” means a compound which reduces or prevents the binding ofIAP proteins to caspase proteins or which reduces or prevents theinhibition of apoptosis by an IAP protein. Alternatively, “inhibitor”means a compound which prevents the binding interaction of X-IAP withcaspases or the binding interaction of ML-IAP with SMAC.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or4) of the substituents listed for that group in which said substituentsmay be the same or different. In an embodiment an optionally substitutedgroup has 1 substituent. In another embodiment an optionally substitutedgroup has 2 substituents. In another embodiment an optionallysubstituted group has 3 substituents.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. “Pharmaceutically acceptable acid addition salt” refers to thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

“Sulfonyl” means a SO₂—R group in which R is H, alkyl, a carbocycle, aheterocycle, carbocycle-substituted alkyl or heterocycle-substitutedalkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are asdefined herein. Particular sulfonyl groups are alkylsulfonyl (i.e.SO₂-alkyl), for example methylsulfonyl; arylsulfonyl, for examplephenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl.

The phrase “and salts and solvates thereof” as used herein means thatcompounds of the inventions may exist in one or a mixture of salts andsolvate forms. For example a compound of the invention may besubstantially pure in one particular salt or solvate form or else may bemixtures of two or more salt or solvate forms.

The present invention provides novel compounds having the generalformula I:

wherein Q, X₁, X₂, Y, Z, R₁, R₂, R₃, R₃′, R₄, R₄′, R₅, R₆, R₆′ and n areas described herein. Compounds of the invention include salts, solvatesand polymorphs thereof unless otherwise specified.

X₁ and X₂ are each independently O or S. In a particular embodiment, X₁and X₂ are both O. In another particular embodiment X₁ and X₂ are bothS. In another particular embodiment, X₁ is S while X₂ is O. In anotherparticular embodiment, X₁ is O while X₂ is S.

Y is a bond, (CR₇R₇)_(m) or S. In an embodiment Y is a bond,(CR₇R₇)_(m), O or S; wherein m is 1 or 2 and R₇ is as defined herein oris H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino,aralkylamino, alkoxy, aryloxy or aralkyloxy. In a particular embodiment,Y is (CHR₇)_(m), O or S; wherein m is 1 or 2 and R₇ is H, halogen,alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamino,alkoxy, aryloxy or aralkyloxy. In a particular embodiment, Y is CH₂. Ina particular embodiment m is 1. In a particular embodiment Y is a bond.In a particular embodiment m is 1 and Y is CHR₇ wherein R₇ isaralkyloxy, for example benzyloxy. In a particular embodiment m is 1 andY is CHR₇ wherein R₇ is F. In a particular embodiment m is 1 and Y isCHR₇ wherein R₇ is aralkylamino, for example benzylamino. In anotherparticular embodiment Y is O. In another particular embodiment Y is S.

Z is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, acarbocycle or a heterocycle; wherein said alkyl, carbocycle andheterocycle is optionally substituted with one or more hydroxyl, alkoxy,acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substitutedalkyl, amino, cyano, nitro, amidino, guanidino an optionally substitutedcarbocycle or an optionally substituted heterocycle; and wherein one ormore CH₂ or CH groups of an alkyl is optionally replaced with —O—, —S—,—S(O)—, S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—,—NR₈—SO₂—, —NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or—O—C(O)—. In an embodiment Z is H, halogen, hydroxyl, carboxyl, amino,nitro, alkyl, a carbocycle or a heterocycle wherein said alkyl,carbocycle and heterocycle are optionally substituted with halogen,hydroxyl, carboxyl, amino, and nitro. In an embodiment Z is H, halogenor alkyl. In an embodiment Z is H. In an embodiment Z is alkyl, forexample methyl, ethyl, propyl and isopropyl. In an embodiment Z isphenyl or naphthyl.

Q is H, halogen, hydroxyl, carboxyl, amino, nitro, cyano, alkyl, acarbocycle or a heterocycle; wherein said alkyl, carbocycle andheterocycle is optionally substituted with one or more hydroxyl, alkoxy,acyl, halogen, mercapto, oxo, carboxyl, acyl, optionally substitutedalkyl, amino, cyano, nitro, amidino, guanidino an optionally substitutedcarbocycle or an optionally substituted heterocycle; and wherein one ormore CH₂ or CH groups of an alkyl is optionally replaced with —O—, —S—,—S(O)—, S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—,—NR₈—SO₂—, —NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or—O—C(O)—. Substituents of the “optionally substituted alkyl”,“optionally substituted carbocycle” and “optionally substitutedheterocycle” are substituted as the foregoing alkyl, carbocycle andheterocycle groups in Q. In a particular embodiment substituents of such“optionally substituted alkyl” are hydroxyl, alkoxy, acyl, halogen,mercapto, oxo, carboxyl, acyl, amino, cyano, nitro, amidino andguanidino. In a particular embodiment such optionally substitutedcarbocycle and heterocycle groups are substituted with hydroxyl, alkyl,alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substitutedalkyl, amino, cyano, nitro, amidino and guanidino. In a particularembodiment Q is a carbocycle or heterocycle optionally substituted withhalogen, amino, oxo, alkyl, a carbocycle or a heterocycle; wherein oneor more CH₂ or CH groups of an alkyl is optionally replaced with —O—,—S—, —S(O)—, S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈-,—NR₈—SO₂—, —NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or—O—C(O)—; and wherein said alkyl, carbocycle or heterocycle isoptionally substituted with halogen, amino, hydroxyl, mercapto,carboxyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylthio, acyloxy,acyloxyalkoxy, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinyl, andalkylsulfinylalkyl. In a particular embodiment Q is a carbocycle or aheterocycle as defined herein which is optionally substituted asdescribed herein while Z is selected from the group consisting of H,halogen, carboxyl, amino, nitro and cyano. In a particular embodiment Qis aryl or heteroaryl while Z is selected from the group consisting ofH, halogen, carboxyl, amino, nitro and cyano. In a particular embodimentZ is H. In another particular embodiment, such other instances of Z isH, halogen or alkyl.

In a particular embodiment, Q is a carbocycle or heterocycle selectedfrom the group consisting of III-1-III-16

wherein n is 1-4, for example 1-3, for example 1-2, for example 1; T isO, S, NR₈ or CR₇R₇; W is O, NR₈ or CR₇R₇; and R₇ and R₈ are as definedherein. In an embodiment, Q has the general formulae III-1 to III-16while Z is selected from the group consisting of H, halogen, carboxyl,amino, nitro and cyano. In a particular embodiment Z is H. In anotherparticular embodiment, Z is H, halogen or alkyl.

In a particular embodiment, Q is a carbocycle or heterocycle selectedfrom the group consisting of IIIa-IIIs:

wherein n is 1-4, for example 1-3, for example 1-2, for example 1; T isO, S, NR₈ or CR₇R₇; W is O, NR₈ or CR₇R₇; and R₇ and R₈ are as definedherein. In a particular embodiment Q is any one of IIIa-IIIi wherein R₈is H and R₇ is selected from the group consisting of H, F, Cl, Me,methoxy, hydroxyethoxy, methoxyethoxy, acetoxyethoxy, methylsulfonylmethylsulfonylmethyl, phenyl and morpholin-4-yl. In another particularembodiment Q is IIId. In a particular embodiment Q is IIId which issubstituted at the 4-position with R₇. In another particular embodimentQ is IIId which is substituted at the 5-position with R₇. In aparticular embodiment Q is F, Me, iPr, phenyl, phenyl substituted asfollows: 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F or 4-F substituted, benzyl,pyrid-3-yl or pyrid-4-yl. In an embodiment, Q has the general formulaeIIIa to IIIs while Z is selected from the group consisting of H,halogen, carboxyl, amino, nitro and cyano. In a particular embodiment Zis H. In another particular embodiment, Z is H, halogen or alkyl.

R₁ is H, OH or alkyl; or R₁ and R₂ together form a 5-8 memberheterocycle. In a particular embodiment, R₁ is H. In a particularembodiment, R₁ and R₂ together form a 6-member ring. In a particularembodiment, R₁ and R₂ together form a 7-member ring. In anotherparticular embodiment, R₁ and R₂ together form an 8-member ring. Inanother particular embodiment, R₁ and R₂ together form a 7-member ringwhile Y is S. In another particular embodiment, R₁ is H, while Y is CH₂.In another particular embodiment, R₁ is H, while Y is S. In anotherparticular embodiment, R₁ is H, while Y is O.

R₂ is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle orheterocyclylalkyl each optionally substituted with halogen, hydroxyl,oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, acyl, alkoxy,alkylthio, sulfonyl, amino and nitro, wherein said alkyl, acyl, alkoxy,alkylthio and sulfonyl are optionally substituted with hydroxy,mercapto, halogen, amino, alkoxy, hydroxyalkoxy and alkoxyalkoxy. In anembodiment, R₂ is alkyl, a carbocycle, carbocyclylalkyl, a heterocycleor heterocyclylalkyl each optionally substituted with halogen, hydroxyl,oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio,sulfonyl, amino and nitro. In a particular embodiment R₂ is alkyl, acarbocycle, carbocyclylalkyl, a heterocycle or heterocyclylalkyl eachoptionally substituted with halogen, hydroxyl, oxo, mercapto, thione,carboxyl, alkyl, haloalkyl, alkoxy, acyl, alkylthio, acyl, hydroxyacyl,methoxyacyl, sulfonyl, amino and nitro. In an embodiment R₂ is alkyl, acarbocycle, carbocyclylalkyl, a heterocycle or heterocyclylalkyl eachoptionally substituted with halogen, hydroxyl, mercapto, carboxyl,alkyl, alkoxy, acyl, amino and nitro. In a particular embodiment R₂ isalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, a heterocycle orheterocyclylalkyl. In a particular embodiment R₂ is alkyl, cycloalkyl ora heterocycle. In a particular embodiment R₂ is selected from the groupconsisting of t-butyl, isopropyl, cyclohexyl, tetrahydropyran-4-yl,N-methylsulfonylpiperidin-4-yl, tetrahydrothiopyran-4-yl,tetrahydrothiopyran-4-yl (in which the S is in oxidized form SO or SO₂),cyclohexan-4-one, 4-hydroxycyclohexane, 4-hydroxy-4-methylcyclohexane,1-methyl-tetrahydropyran-4-yl, 2-hydroxyprop-2-yl, but-2-yl,thiophen-3-yl, piperidin-4-yl, N-acetylpiperidin-4-yl,N-hydroxyethylpiperidin-4-yl, N-(2-hydroxyacetyl)piperidin-4-yl,N-(2-methoxyacetyl)piperidin-4-yl, pyridin-3-yl, phenyl,tetrahydrofuran-2-yl-carbonyl, methoxyethanone, 2-methoxyethoxyethanoneand 1-hydroxyeth-1-yl. In an embodiment of the invention R₂ is t-butyl,isopropyl, cyclohexyl, cyclopentyl, phenyl or tetrahydropyran-4-yl. In aparticular embodiment, R₂ is phenyl. In a particular embodiment, R₂ iscyclohexyl. In another embodiment R₂ is tetrahydropyran-4-yl. In anotherparticular embodiment, R₂ is isopropyl (i.e. the valine amino acid sidechain). In another particular embodiment, R₂ is t-butyl. In a particularembodiment R₂ is oriented such that the amino acid, or amino acidanalogue, which it comprises is in the L-configuration.

R₃ is H or alkyl optionally substituted with halogen or hydroxyl; or R₃and R₄ together form a 3-6 heterocycle. In an embodiment R₃ is H oralkyl; or R₃ and R₄ together form a 3-6 heterocycle. In an embodiment R₃is H or methyl, ethyl, propyl or isopropyl. In a particularly particularembodiment R₃ is H or methyl. In another particular embodiment R₃ ismethyl. In another particular embodiment R₃ is fluoromethyl. In anotherparticular embodiment, R₃ is ethyl. In another particular embodiment R₃is hydroxyethyl. In a particular embodiment R₃ is fluoromethyl. In aparticular embodiment R₃ is hydroxyethyl. In another embodiment R₃ isoriented such that the amino acid, or amino acid analogue, which itcomprises is in the L-configuration. In a particular embodiment R₃ andR₄ together with the atoms from which they depend form a 3-6heterocycle. In a particular embodiment R₃ and R₄ together form anazetidine ring. In a particular embodiment R₃ and R₄ together form apyrrolidine.

R₃′ is H, or R₃ and R₃′ together form a 3-6 carbocycle. In anembodiment, R₃′ is H. In another embodiment R₃ and R₃′ together form a3-6 carbocycle, for example a cyclopropyl ring. In a particularembodiment R₃ and R₃′ are both methyl.

R₄ and R₄′ are independently H, hydroxyl, amino, alkyl, carbocycle,carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl,heterocycle, heterocycloalkyl, heterocycloalkyloxy orheterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl,carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle,heterocycloalkyl, heterocycloalkyloxy and heterocycloalkyloxycarbonyl isoptionally substituted with halogen, hydroxyl, mercapto, carboxyl,alkyl, alkoxy, amino, imino and nitro; or R₄ and R₄′ together form aheterocycle. In an embodiment R₄ and R₄′ are independently H, hydroxyl,amino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, orheteroarylalkyl wherein each alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl and heteroarylalkyl is optionallysubstituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy,amino and nitro; or R₄ and R₄′ together form a heterocycle. In aparticular embodiment R₄ and R₄′ together form a heterocycle, forexample an azetidine ring, or a pyrrolidine ring. In a particularembodiment R₄ and R₄′ are both H. In another particular embodiment R₄ ismethyl and R₄′ is H. In a particular embodiment one of R₄ and R₄′ ishydroxyl (OH) while the other is H. In another embodiment, one of R₄ andR₄′ is amino, such as NH₂, NHMe and NHEt, while the other is H. In aparticular embodiment, R₄′ is H and R₄ is H, allyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroaryl or heteroarylalkyl. In aparticular embodiment R₄ is a group selected from the group consistingof:

R₅ is H or alkyl. In a particular embodiment, R₅ is H or methyl. In aparticular embodiment, R₅ is H. In another particular embodiment, R₅ ismethyl.

R₆, and R₆′ are each independently H, alkyl, aryl or aralkyl. In aparticular embodiment, R₆ is alkyl, for example methyl. In anotherparticular embodiment R₆ is aryl, for example phenyl. In anotherparticular embodiment R₆ is aralkyl, for example benzyl. In a particularembodiment R₆ and R₆′ are the same, for example both alkyl, e.g. bothmethyl. In another particular embodiment R₆ is methyl and R₆′ is H.

R₇ in each occurrence is independently H, cyano, hydroxyl, mercapto,halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, aheterocycle or —U—V; wherein U is —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—,—C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—,—NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)— and V is alkyl, acarbocycle or a heterocycle; and wherein one or more CH₂ or CH groups ofan alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—,—C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈-, —NR₈—SO₂-, —NR₈—C(O)—NR₈—,—NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)—; and an alkyl,carbocycle and heterocycle is optionally substituted with hydroxyl,alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substitutedalkyl, amino, cyano, nitro, amidino, guanidino an optionally substitutedcarbocycle or an optionally substituted heterocycle. Substituents of the“optionally substituted carbocycle” and “optionally substitutedheterocycle” are as defined herein. In a particular embodiment suchcarbocycle and heterocycle groups are substituted with hydroxyl, alkyl,alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substitutedalkyl, amino, cyano, nitro, amidino and guanidino. In an embodiment R₇is H, halogen, alkyl, haloalkyl, aryl, aralkyl, amino, arylamino,alkylamino, aralkylamino, alkoxy, alkoxyalkoxy, aryloxy or aralkyloxy.

R₈ is H, alkyl, a carbocycle or a heterocycle wherein one or more CH₂ orCH groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—,S(O)₂, —N(R₈), or —C(O)—; and said alkyl, carbocycle and heterocycle isoptionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto,oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano nitro,amidino, guanidino an optionally substituted carbocycle or an optionallysubstituted heterocycle. Substituents of the “optionally substitutedcarbocycle” and “optionally substituted heterocycle” are as definedherein. In a particular embodiment such carbocycle and heterocyclegroups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen,mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano,nitro, amidino and guanidino. In a particular embodiment R₈ is H, alkyl,or acyl. In an embodiment R₈ is methyl. In another embodiment R₈ isacetyl. In a particular embodiment R₈ is H. In an embodiment R₇ is H,halogen, amino, hydroxyl, carboxyl, alkyl, haloalkyl or aralkyl. In aparticular embodiment R₇ is halogen, for example Cl or F. In aparticular embodiment R₇ is H. It is understood that substitutionsdefined for R₇ and R₈ as well as all other variable groups herein aresubject to permissible valency.

m is 0 to 4. In an embodiment m is 0. In an embodiment m is 1. In anembodiment m is 2. In an embodiment m is 3. In an embodiment m is 4.

Compounds of the invention contain one or more asymmetric carbon atoms.Accordingly, the compounds may exist as diastereomers, enantiomers ormixtures thereof. The syntheses of the compounds may employ racemates,diastereomers or enantiomers as starting materials or as intermediates.Diastereomeric compounds may be separated by chromatographic orcrystallization methods. Similarly, enantiomeric mixtures may beseparated using the same techniques or others known in the art. Each ofthe asymmetric carbon atoms may be in the R or S configuration and bothof these configurations are within the scope of the invention. In aparticular embodiment, compounds of the invention have the followingstereochemical configuration of formula I′

wherein X₁, X₂, Y, Z, Q R₁, R₂, R₃, R₄, R₄′, R₅, R₆ and R₆′ are asdescribed herein.

In particular embodiments, compounds of the invention have the generalformula IIa-IId

wherein X₁, X₂, Y, Z, Q R₁, R₂, R₃, R₄, R₄′, R₅, R₆, R₆′ and R₇ are asdescribed herein.

The invention also encompasses prodrugs of the compounds describedabove. Suitable prodrugs where applicable include known amino-protectingand carboxy-protecting groups which are released, for examplehydrolyzed, to yield the parent compound under physiologic conditions. Aparticular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy (OH) group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group and asdefined above or a group having the formula —C(O)—O—CP1P2-haloalkyl,where P1 and P2 are the same or different and are H, lower alkyl, loweralkoxy, cyano, halo lower alkyl or aryl. In a particular embodiment, thenitrogen atom is one of the nitrogen atoms of the amidino group of thecompounds of the invention. These prodrug compounds are preparedreacting the compounds of the invention described above with anactivated acyl compound to bond a nitrogen atom in the compound of theinvention to the carbonyl of the activated acyl compound. Suitableactivated carbonyl compounds contain a good leaving group bonded to thecarbonyl carbon and include acyl halides, acyl amines, acyl pyridiniumsalts, acyl alkoxides, in particular acyl phenoxides such asp-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, anddifluorophenoxy acyl. The reactions are generally exothermic and arecarried out in inert solvents at reduced temperatures such as −78 toabout 50 C. The reactions are usually also carried out in the presenceof an inorganic base such as potassium carbonate or sodium bicarbonate,or an organic base such as an amine, including pyridine, triethylamine,etc. One manner of preparing prodrugs is described in U.S. Ser. No.08/843,369 filed Apr. 15, 1997 (corresponding to PCT publicationWO9846576) the contents of which are incorporated herein by reference intheir entirety.

Particular compounds of formula I include the following:

Compounds of the invention may exist in different resonance forms andthat all such resonance forms are within the scope of the inventionherein.

Synthesis

Compounds of the invention are prepared using standard organic synthetictechniques from commercially available starting materials and reagents.It will be appreciated that synthetic procedures employed in thepreparation of compounds of the invention will depend on the particularsubstituents present in a compound and that various protection anddeprotection steps that are standard in organic synthesis may berequired but may not be illustrated in the following general schemes. Ina particular general synthetic scheme, compounds of the invention may beprepared by coupling amino acid residue analogues employing typicalamide coupling procedures. In scheme 1, wherein Q, Y, Z, R₁, R₆ and R₆′are as defined herein and Pr is a suitable protecting group,amine-protected amino acid residue analogues are coupled and deprotectedsequentially to give the final compounds.

It will be appreciated that the amino acid analogs may be coupled in anyorder and may be prepared using solid phase support which is routine inthe art. For example, Scheme 2 illustrates an alternative amino acidresidue analogue coupling route.

Imidazo[1,2a]pyridine intermediates may be prepared according to scheme3 wherein Q, Y, Z, R₁, R₆ and R₆′ are as defined herein. Startingbromine a is reacted with 2-aminopyridyl b to give protected compound cwhich is subsequently deprotected to give intermediate d employed insynthesis of compounds of the invention.

Compounds of the invention in which R₄ or R₄′ are other than H may beprepared according to standard organic chemistry techniques, for exampleby reductive amination in which a starting amino acid residue analoge.g. NH₂—CH(R₃)—C(O)—OH is reacted with a suitable aldehyde or ketone togive the desired R₄ and R₄′ substituents. See scheme 4. The resultingR₄/R₄′ substituted amino acid intermediate can then be conjugated to thenext amino acid intermediate or the remainder of the compound usingstandard peptide coupling procedures.

In a particular embodiment, alanine is reacted with1-methylindole-2-carboxaldehyde and reduced with sodium cyanoborohydridedissolved in 1% HOAc/DMF to give the N-substituted alanine residue whichmay be used in preparing compounds of the invention. See scheme 5.

Alternatively, the reductive amination procedure to introduce R_(4/)R₄′substituents is the final step in the preparation of the compound.

When compounds of the invention incorporate R₄ or R₄′ substituents otherthan H, they may also be prepared by substitution of a suitable acidintermediate which incorporates a leaving group with a desired amine.For example Br—CH(R₃)—C(O)—OH is substituted with an amine R₄—NH₂ orR₄—NH—R₄′ according to scheme 6.

Alternatively, the substitution reaction introducing R₄ or R₄′substituents may be performed as a final step in the preparation of thecompound as illustrated in scheme 7.

In a particular embodiment, the following amines used in schemes 6 and7:

Compounds of the invention in which either X₁ or X₂ is sulfur, i.e. thecompound incorporates a thioamide, may be prepared according toestablished organic chemistry techniques. For example, compounds inwhich X₂ is sulfur can be prepared according to scheme 8 starting froman Fmoc protected amino acid residue analog NH₂—CH(R₂)—COOH which isdissolved in THF and cooled to −25° C., with addition of DIPEA followedby addition of isobutylchloroformate. After 10 minutes, the diamine,4-nitrobenzene-1,2-diamine, is added and the reaction mixture iscontinuously stirred at −25° C. for 2 hours, then at room temperatureovernight. THF is vacuumed off and the mixture is then subjected toflash chromatography using 50% EtOAc/Hexane to yield the product. TheFmoc-alanine derivative, phosphorus pentasulfide and sodium carbonateare mixed in THF and stirred overnight. The solution is concentrated anddirect chromatography using 80% EtOAc/Hexane yields the activatedthioalanine. The activated thioalanine and sodium nitrite are then mixedin acetic acid and diluted with H₂O. The resulting precipitant isfiltered and dried to yield the product. The thioalanine is coupled toan A ring substituted proline amino acid residue analog by dissolvingboth in DMF. The thioamide product may then be deprotected with 20%PIP/DMA for 15 minutes and used to conjugate to theR₄/R₄′—N—C(R₃)(R₃′)—COOH. Alternatively the Fmoc-protected thioamide isfirst coupled to the A ring substituted proline amino acid residueanalog followed by Fmoc deprotection and subsequent coupling to theR₄/R₄′—R₄/R₄′—N—C(R₃)(R₃′)—COOH amino acid residue analog.

Indications

The compounds of the invention inhibit the binding of IAP proteins tocaspases, in particular X-IAP binding interaction with caspases 3 and 7.The compounds also inhibit the binding of ML-IAP to Smac protein.Accordingly, the compounds of the invention are useful for inducingapoptosis in cells or sensitizing cells to apoptotic signals, inparticular cancer cells. Compounds of the invention are useful forinducing apoptosis in cells that overexpress IAP proteins.Alternatively, compounds of the invention are useful for inducingapoptosis in cells in which the mitochondrial apoptotic pathway isdisrupted such that release of Smac from ML-IAP proteins is inhibited,for example by up regulation of Bcl-2 or down regulation of Bax/Bak.More broadly, the compounds can be used for the treatment of all cancertypes which fail to undergo apoptosis. Examples of such cancer typesinclude neuroblastoma, intestine carcinoma such as rectum carcinoma,colon carcinoma, familiary adenomatous polyposis carcinoma andhereditary non-polyposis colorectal cancer, esophageal carcinoma, labialcarcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma,salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullarythyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma,kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterinecorpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma,bronchial carcinoma, small cell lung carcinoma, non-small cell lungcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma and plasmocytoma.

Compounds of the invention are useful for sensitizing cells to apoptoticsignals. Accordingly, the compounds may be administered prior to,concomitantly with, or following administration of radiation therapy orcytostatic or antineoplastic chemotherapy. Suitable cytostaticchemotherapy compounds include, but are not limited to (i)antimetabolites, such as cytarabine, fludarabine,5-fluoro-2′-deoxyuiridine, gemcitabine, hydroxyurea or methotrexate;(ii) DNA-fragmenting agents, such as bleomycin, (iii) DNA-crosslinkingagents, such as chlorambucil, cisplatin, cyclophosphamide or nitrogenmustard; (iv) intercalating agents such as adriamycin (doxorubicin) ormitoxantrone; (v) protein synthesis inhibitors, such as L-asparaginase,cycloheximide, puromycin or diphtheria toxin; (Vi) topoisomerase Ipoisons, such as camptothecin or topotecan; (vii) topoisomerase IIpoisons, such as etoposide (VP-16) or teniposide; (viii)microtubule-directed agents, such as colcemid, colchicine, paclitaxel,vinblastine or vincristine; (ix) kinase inhibitors such as flavopiridol,staurosporin, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine);(x) miscellaneous investigational agents such as thioplatin, PS-341,phenylbutyrate, ET-18-OCH₃, or farnesyl transferase inhibitors(L-739749, L-744832); polyphenols such as quercetin, resveratrol,piceatannol, epigallocatechine gallate, theaflavins, flavanols,procyanidins, betulinic acid and derivatives thereof; (xi) hormones suchas glucocorticoids or fenretinide; (xii) hormone antagonists, such astamoxifen, finasteride or LHRH antagonists. In a particular embodiment,compounds of the present invention are coadministered with a cytostaticcompound selected from the group consisting of cisplatin, doxorubicin,taxol, taxotere and mitomycin C. In a particular embodiment, thecytostatic compound is doxorubicin.

Another class of active compounds which can be used in the presentinvention are those which are able to sensitize for or induce apoptosisby binding to death receptors (“death receptor agonists”). Such agonistsof death receptors include death receptor ligands such as tumor necrosisfactor a (TNF-α), tumor necrosis factor β (TNF-β, lymphotoxin-α), LT-β(lymphotoxin-β), TRAIL (Apo2L, DR4 ligand), CD95 (Fas, APO-1) ligand,TRAMP (DR3, Apo-3) ligand, DR6 ligand as well as fragments andderivatives of any of said ligands. In an embodiment, the death receptorligand is TNF-α. In a particular embodiment, the death receptor ligandis Apo2L/TRAIL. Furthermore, death receptors agonists comprise agonisticantibodies to death receptors such as anti-CD95 antibody, anti-TRAIL-R1(DR4) antibody, anti-TRAIL-R2 (DR5) antibody, anti-TRAIL-R3 antibody,anti-TRAIL-R4 antibody, anti-DR6 antibody, anti-TNF-R1 antibody andanti-TRAMP (DR3) antibody as well as fragments and derivatives of any ofsaid antibodies.

For the purpose of sensitizing cells for apoptosis, the compounds of thepresent invention can be also used in combination with radiationtherapy. The phrase “radiation therapy” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.Radiation therapy is based on the principle that high-dose radiationdelivered to a target area will result in the death of reproducing cellsin both tumor and normal tissues. The radiation dosage regimen isgenerally defined in terms of radiation absorbed dose (rad), time andfractionation, and must be carefully defined by the oncologist. Theamount of radiation a patient receives will depend on variousconsideration but the two most important considerations are the locationof the tumor in relation to other critical structures or organs of thebody, and the extent to which the tumor has spread. Examples ofradiotherapeutic agents are provided in, but not limited to, radiationtherapy and is known in the art (Hellman, Principles of RadiationTherapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devitaet al., 4th ed., vol 1, 1993). Recent advances in radiation therapyinclude three-dimensional conformal external beam radiation, intensitymodulated radiation therapy (IMRT), stereotactic radiosurgery andbrachytherapy (interstitial radiation therapy), the latter placing thesource of radiation directly into the tumor as implanted “seeds”. Thesenewer treatment modalities deliver greater doses of radiation to thetumor, which accounts for their increased effectiveness when compared tostandard external beam radiation therapy.

Ionizing radiation with beta-emitting radionuclides is considered themost useful for radiotherapeutic applications because of the moderatelinear energy transfer (LET) of the ionizing particle (electron) and itsintermediate range (typically several millimeters in tissue). Gamma raysdeliver dosage at lower levels over much greater distances. Alphaparticles represent the other extreme, they deliver very high LETdosage, but have an extremely limited range and must, therefore, be inintimate contact with the cells of the tissue to be treated. Inaddition, alpha emitters are generally heavy metals, which limits thepossible chemistry and presents undue hazards from leakage ofradionuclide from the area to be treated. Depending on the tumor to betreated all kinds of emitters are conceivable within the scope of thepresent invention.

Furthermore, the present invention encompasses types of non-ionizingradiation like e.g. ultraviolet (UV) radiation, high energy visiblelight, microwave radiation (hyperthermia therapy), infrared (IR)radiation and lasers. In a particular embodiment of the presentinvention UV radiation is applied.

The invention also includes pharmaceutical compositions or medicamentscontaining the compounds of the invention and a therapeutically inertcarrier, diluent or excipient, as well as methods of using the compoundsof the invention to prepare such compositions and medicaments.Typically, the compounds of formula I used in the methods of theinvention are formulated by mixing at ambient temperature at theappropriate pH, and at the desired degree of purity, withphysiologically acceptable carriers, i.e., carriers that are non-toxicto recipients at the dosages and concentrations employed into agalenical administration form. The pH of the formulation depends mainlyon the particular use and the concentration of compound, but may rangeanywhere from about 3 to about 8. Formulation in an acetate buffer at pH5 is a suitable embodiment. In an embodiment, the inhibitory compoundfor use herein is sterile. The compound ordinarily will be stored as asolid composition, although lyophilized formulations or aqueoussolutions are acceptable.

The composition of the invention will be formulated, dosed, andadministered in a fashion consistent with good medical practice. Factorsfor consideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governedby such considerations, and is the minimum amount necessary to inhibitIAP interaction with caspases, induce apoptosis or sensitize a malignantcell to an apoptotic signal. Such amount is may be below the amount thatis toxic to normal cells, or the mammal as a whole.

Generally, the initial pharmaceutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, for example about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. Oral unit dosage forms, such as tablets andcapsules, may contain from about 25 to about 1000 mg of the compound ofthe invention.

The compound of the invention may be administered by any suitable means,including oral, topical, transdermal, parenteral, subcutaneous,intraperitoneal, intrapulmonary, and intranasal, and, if desired forlocal treatment, intralesional administration. Parenteral infusionsinclude intramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. An example of a suitable oral dosage formis a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg ofthe compound of the invention compounded with about 90-30 mg anhydrouslactose, about 5-40 mg sodium croscarmellose, about 5-30 mgpolyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.The powdered ingredients are first mixed together and then mixed with asolution of the PVP. The resulting composition can be dried, granulated,mixed with the magnesium stearate and compressed to tablet form usingconventional equipment. An aerosol formulation can be prepared bydissolving the compound, for example 5-400 mg, of the invention in asuitable buffer solution, e.g. a phosphate buffer, adding a tonicifier,e.g. a salt such sodium chloride, if desired. The solution is typicallyfiltered, e.g. using a 0.2 micron filter, to remove impurities andcontaminants.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. Reagents and solvents were obtained fromcommercial sources and used as received. Unjless otherwise noted,chromatographic purifications were performed using pre-packed silica gelcolumns on a CombiFlash Companion system by Teledyne-Isco, Inc. Lincoln,Nebr. The identity and purity of compounds were checked by LCMS and ¹HNMR analysis.

Abbreviations used herein are as follows:

AcOH: acetic acid;

ACN: acetonitrile;

Chg: cyclohexylglycine;

DCM: dichloromethane

DIPEA: diisopropylethylamine;

DMAP: 4-dimethylaminopyridine;

DME: 1,2-dimethoxyethane;

DMF: dimethylformamide;

DMSO: dimethylsulfoxide

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline;

EtOAc: ethylacetate

EtOH: ethanol;

LCMS: liquid chromatography mass spectrometry;

HATU: O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;

HOBt: N-Hydroxybenzotriazole

HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-Tetramethyl-uroniumHexafluorophosphate;

HPLC: high performance liquid chromatography;

MeOH: methanol;

NBS: N-bromosuccinamide;

TASF: tris(dimethylamino)sulfonium difluorotrimethylsilicate;

TEA: triethylamine;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

Example 1 2-[tert-Butoxycarbonyl-(1H-pyrrol-2-ylmethyl)-amino]-propionicacid

Alanine ethyl ester b (5 g, 32.5 mmol), pyrrole-2-carboxaldehyde a (3.1g, 32.5 mmol), sodium cyanoborohydride (2.04 g, 32.5 mmol) and AcOH (1%)were mixed in DMF and stirred overnight. The reaction was quenched withH₂O, and DMF was evaporated. The mixture was diluted with EtOAc, washedby 0.1N NaOH, dried and concentrated to yield product c 2.5 g. Theresulting ester c (2.5 g, 12.8 mmol), di-tert-butyldicarbonate (3.06 g,14 mmol) were mixed in THF, H₂O with NaHCO₃ and stirred overnight. THFwas evaporated, and the mixture was diluted with EtOAc, washed by 1NNaOH, sat. NH₄Cl and brine. After dried, the mixture was concentrated toyield the Boc-protected ester d 3.3 g. The Boc-protected ester d (1.67g, 5.6 mol), lithium hydroxide mono hydrate (284 mg, 6.77 mmol) weremixed in THF and H₂O at 0° C. THF was vacuumed off, and the solution wasacidified by dilute H₂SO₄, extracted by EtOAc twice. Organic layers werecombined, dried and evaporated giving product2-[tert-butoxycarbonyl-(1H-pyrrol-2-ylmethyl)-amino]-propionic acid e.

Example 2 Tetrahydropyranylglycine

Tetrahydropyranylglycine was purchased from NovaBiochem, or synthesizedaccording to the literature: Ghosh, A. K.; Thompson, W. J.; holloway, M.K.; McKee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M.;Wai, J. M; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleife, W. A.;Huff, J. R.; Anderson, P. S. J. Med. Chem., 1993, 36, 2300-2310.

Example 3 Piperidinylglycine

Piperidinylglycine was synthesized according to the procedures describedby Shieh et al. (Tetrahedron: Asymmetry, 2001, 12, 2421-2425.

Example 4 4,4-difluorocyclohexylglycine

4,4-difluorocyclohexylglycine was made according to the proceduresdescribed in patent application US 20030216325.

Example 5 Boc (S)-2-amino-2-(4-hydroxycyclohexyl)acetic acid

Following the procedure described by Sheih et al. (Tetrahedron:Asymmetry, 2001, 12, 2421-2425), a solution of ketone a (8.4 g) andEtOAc (30 mL) was added to a solution of N-Cbz-phosphonoglycine methylester b, TMG (4.5 mL) and EtOAc (30 mL). The solution was maintained atrt for 48 h, then washed with 1N HCl (3×50 mL), brine (1×50 mL) dried(Na₂SO₄), filtered, and concentrated. The residue was adsorbed ontoCelite, and purified by chromatography, then further purified byre-crystallization from EtOAc/hexanes to afford 5.2 g of product c.

Following the procedure described by Sheih, (Tetrahedron: Asymmetry,2001, 12, 2421-2425), a solution of eneamide c (5.0 g),(S,S)-Me-BPE-Rh(I) (1.5 g, Strem Chemicals, Newburyport, Mass.), andMeOH (100 mL) was shaken virgorously under 70 psi of H₂ for 48 h. Thesolvent was removed under reduced pressure. The residue was taken up inEtOAc, and filtered through SiO₂ with more EtOAc. The solvent wasremoved under reduced pressure to afford 4.0 g of product d as acolorless solid.

A mixture of Cbz-carbamate d, (4.0 g) Boc₂O, (2.9 g), 20% Pd(OH)₂.C (1.0g) and MeOH (30 mL) was maintained under an atmosphear of H₂ for 6 h.The mixture was filtered through Celite with MeOH. The solvent wasremoved under reduced pressure to afford 4.5 g of residue e, which wastaken on directly.

The residue e from above was dissolved in H₂O (10 mL), AcOH (30 mL), THF(5 mL), and dichloroacetic acid (3 mL) and maintained at rt overnight.Water (5 mL) was added and the solution and maintaned until hyrolysiswas complete, as monitored by HPLC-MS. Solid Na₂CO₃ was added cautiouslyuntil gas evolution ceased, the mixture was diluted with aq NaHCO₃, andextracted with 10% EtOAc/DCM. The combined organic phases were washedonce with brine, dried (Na₂SO₄), filtered, and concentrated. The residuewas purified by chromatography to afford 2.9 g of product f.

A mixture of ketone f (1.5 g) MeOH (50 ml) was treated with NaBH4 (290mg) at 0° C. for 20 min. The mixture was acidifed to ˜pH1 with 10% aqcitric acid and the MeOH was removed under reduced pressure. The residuewas diluted with water and extraced with 20% EtOAc/DCM. The combinedorganic phases were washed once with brine, dried (Na₂SO₄), filtered,and concentrated. The residue was purified by chromatography to afford1.17 g of product g and 0.23 g of product h.

A mixture of ester g (1.17 g) LiOH.H2O (160 mg), THF (3 mL) and water(4.5 mL) was stirred vigorously at rt overnight. The mixture was dilutedwith brine and exaustivly extraced with EtOAc. The combined organicphases were washed once with brine, dried (Na₂SO₄), filtered, andconcentrated to afford acid i (525 mg).

Example 6 N-Boc-N-cyclopropylmethyl-L-alanine

L-alanine methyl ester hydrochloride a (5 g, 35.8 mmol) andcyclopropanecarboxaldehyde b (2.67 ml, 35.8 mmol) were suspended in 50ml THF w/1% AcOH. Addition of 5 ml of CH₃OH made the cloudy solutionturned to clear. NaCNBH₄ (2.25 g, 35.8 mmol) was added and the reactionmixture stirred overnight. The reaction was quenched by addition of 1Naq. NaOH, extracted by EtOAc twice, organic layers were dried overNa₂SO₄ and concentrated to dryness. The crude material was purified bychromatography using 30% EtOAc/hexane (stained by ninhydrin) to obtainthe compound c (1 g, 18%). The compound c (1 g, 6.37 mmol) anddi-t-bocdicarbonate (2.1 g, 9.55 mmol) were diluted in THF (20 ml) andH₂O (20 ml), NaHCO₃ (1.3 g, 15.9 mmol) was added. The reaction mixturestirred overnight for completion. THF was removed under reducedpressure, and the aqueous layer was extracted by EtOAc 3 times. Combinedorganic layers were washed by 1N NaOH, sat, NH₄Cl followed by brine, theconcentrated to dryness. The Boc-protected compound d (1.39 g, 5.40mmol) was stirred with LiOH.H₂O (1.14 g, 27 mmol) in THF (20 ml) and H₂O(20 ml) overnight at room temperature. THF was stripped off, and theaqueous layer was adjusted to pH=4 by adding 10% citric acid, thenextracted by EtOAc 3 times. Combined organic layers were washed by brineand concentrated. The crude was purified by reverse phase C-18 columneluted by 0%-50% acetonitrile/H₂O to give pure compound e as a whitesolid (794 mg).

Example 7 N-Boc-N-methyl-L-alanine-L-cyclohexylglycine

A solution of Fmoc-L-cyclohexylglycine (3.6 g, 9.6 mmol) dissolved inDCM (50 mL) and DIPEA (5.6 mL, 32 mmol) was added to 2-chlorotritylchloride resin (5 g, 8 mmol) and gently agitated for 3 hours at roomtemperature. The resin was washed with DCM 4 times, DCM/MeOH/DIPEA(17:2:1) 3 times, DCM 3 times, and 2 times dimethylacetamide (DMA). TheFmoc group was removed by treating the resin with 20% piperidine/DMA (50mL) for 15 minutes. The resin was washed with DMA 6 times. A solution ofBoc-N-methylalanine (3.3 g, 16 mmol), HBTU (6.1 g, 16 mmol), and DIPEA(5.6 mL, 32 mmol) and DMA/DCM (1:1, 50 mL) was added to the resin andgently agitated for 2 hours at room temperature. The resin was washedwith DMA 5 times, DCM 2 times, and dried under reduced pressure. Thedipeptide was cleaved from the resin by gentle agitation withHOAc/TFE/DCM (1:1:3, 100 mL) for 2 hours at room temperature. The resinwas removed by filtration and the solution concentrated. Residual AcOHwas removed by azeotroping with hexanes (15 times volume). The solidresidue was purified by reverse-phase HPLC (C₁₈, MeCN—H₂O, 0.1% TFA) andthe solvents removed by lyophylization to provide 1.2 g (43%) ofdipeptide N-Boc-N-methyl-L-alanine-L-cyclohexylglycine as a whitepowder.

Example 8 N-Boc-N-methyl-L-alanine-L-dehydropyranylglycine

A mixture of N-Cbz-dehydropyranylglycine methyl ester a (Burk, M. J.;Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375, andreferences therein) (5.2 g, 17 mmol), 5% Pd.C (500 mg), MeOH (75 mL) andTHF (25 mL) was maintained under an atmosphere of H₂ for 24 h. Themixture was filtered through Celite and the Celite washed with MeOH, andconcentrated under reduced pressure to afford a quantitative yield ofamine b as a colorless oil, which was carried on directly.

The amine b prepared above was combined with CH₂Cl₂ (40 mL), saturatedaqueous NaHCO₃ (40 mL) and cooled to 0° C. Benzyloxy carbonyl chloride(3.0 mL) was then added dropwise and the mixture stirred vigorouslyovernight. The phases were separated and the aqueous phase extractedwith CH₂Cl₂ (3×20 mL). The combined organic phases were washed withbrine (1×50 mL), dried (Na₂SO₄), filtered, adsorbed onto Celite andchromatographed (ISCO, 120 g silica column, gradient elution 5-55%EtOAc-hexanes) to afford 4.15 g (80%) of racemic Cbz-pyranylglycinemethyl ester. The enantiomers were separated on a Chiracel OD columneluting with 10% EtOH-hexanes. The desired S-enantiomer c elutes firstunder these conditions.

A mixture of (S)—N-Cbz-pyranyl glycine c methyl ester (2.4 g, 7.82 mmol)10% Pd.C (700 mg), MeOH (80 mL) was maintained under 1 atmosphere of H₂for 24 h. The mixture was filtered through Celite with MeOH, andconcentrated under reduced pressure to afford 1.35 g (100%) of amine das a colorless oil. Alternatively, pyranyl glycine can be synthesized inenantiopure form following the procedure of Ghosh (Ghosh, A. K.;Thompson, W. J.; Holloway, M. K.; McKee, S. P.; Duong, T. T.; Lee, H.Y.; Munson, P. M.; Smith, A. M.; Wai, J. M.; Darke, P. L.; Zugay, J. A.;Imini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med.Chem., 1993, 36, 2300).

A mixture of amine d (1.35 g, 7.8 mmol), N-Boc-N-methyl alanine e (1.74g, 8.6 mmol), EDC (1.65 g 8.8 mmol) and MeCN (50 mL) was maintained atrt overnight. The MeCN was removed under reduced pressure, and theresidue diluted with EtOAc, washed with 0.5 N HCl (3×10 mL), 0.5 N NaOH(3×10 mL), dried (MgSO₄), filtered, and concentrated to provide 2.1 g(75%) of protected dipeptide f, as a clear oil.

To a 0° C. solution of ester f (2.10 g, 5.86 mmol) and THF (50 mL) wereadded LiOH.H₂O (1.23 g, 29.3 mmol) and water (2 mL). The mixture wasmaintained at 0° C. for 2 h, then the cooling bath was removed and themixture was stirred overnight. Most of the THF was then removed underreduced pressure and the residue was diluted with CH₂Cl₂, washed with0.5 N HCl, dried (MgSO₄), filtered, and concentrated to provide 1.53 g(78%) of dipeptide N-Boc-N-methyl-L-alanine-L-dehydropyranylglycine g,as a colorless solid.

Example 9 N-Boc-protected Cyclic Sulfonyl Amino Acid

Sulfide a (810 mg, 2.5 mmol), synthesized according to the generalprocedure of Shieh [Shieh, W-C.; Xue, S.; Reel, N.; Wu, R.; Fitt, J.;Repic, O. Tetrahedron: Asymmetry, 2001, 12, 2421-2425], was dissolved inmethanol (25 mL). Oxone (4.5 g) was dissolved in deionized water (25mL). The methanol solution of substrate was cooled to −10° C., and theaqueous solution of oxone was added to the reaction slowly. The reactionwas kept on ice and gradually allowed to warm to room temperature whilestirring overnight. Deionized water was used to dilute the reaction toapproximately 150 mL, then poured into 90% ethyl acetate-hexanes forextraction. The organic phase was dried (Na₂SO₄), adsorbed onto Celiteand purified by chromatography ISCO CombiFlash 40 g column, 5-90% ethylacetate-hexanes over 30 min to afford 804 mg (2.27 mmol, 91%) of theproduct sulfone b.

Following the general procedure of Burk [Burk, M. J.; Gross, M. F.;Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375-9376.], alkene b (774mg 2.19 mmol), dry methanol (40 mL), and [(S,S)-Me-BPE-Rh(COD)]⁺OTf⁻(500 mg, 0.8 mmol) were mixed in a Parr shaker flask purged withnitrogen. The Parr flask was evacuated and subsequently charged to 60psi with hydrogen gas and shaken vigorously overnight. Methanol wasremoved under reduced pressure, and crude product was filtered through asmall plug of silica gel using ethyl acetate. Evaporation of the solventyielded 730 mg (2.0 mmol, 94%) of product c with >98% yield.

Z-protected amino ester c (804 mg, 2.27 mmol) was dissolved in methanol(16 mL). To this solution was added BOC-anhydride (1.5 g, 6.8 mmol),followed by 20% Pd(OH)₂.C (250 mg). All air was removed from thereaction flask by house vacuum, and the mixture was stirred vigorouslyfor 5 min. The flask was then filled with hydrogen gas and allowed tostir vigorously at room temperature for 6 h. After evacuating thehydrogen atmosphere, the mixture was filtered through Celite usingmethanol, and crude product d was obtained by evaporation of the solvent(508 mg, 1.56 mmol, 70% yield).

Ester d (508 mg, 1.56 mmol) was dissolved in 8 mL of THF. Deionizedwater (4 mL) was added, followed by LiOH.H₂O (120 mg, 2.8 mmol). Themixture was stirred at room temperature overnight, acidified usingaqueous 1 N HCl and extracted into ethyl acetate (3×25 mL). The organicextracts were dried further with Na₂SO₄, filtered and concentrated togive 372 mg (1.21 mmol, 78% yield) of the N-Boc-protected cyclicsulfonyl amino acid e, which was carried on without purification.

Example 10 N-Boc-N-methyl-L-glycine

Following the general procedure of Grigg [Blaney, P.; Grigg, R.;Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58,1719-1737] a roundbottom flask was charged with sodium hydride (480 mg60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogenfor 15 min. THF (6.0 mL) was added to the flask, and the suspension wascooled to 0° C. using an ice water bath. A separate flask was chargedwith BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide(1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaHsuspension in THF, with vigorous stirring at 0° C. After 1 h ofstirring, the reaction was warmed to room temperature and allowed tostir overnight. The reaction was again cooled to 0° C., and methanol (4mL) was added very slowly to quench the excess hydride. Deionized waterwas added to dilute the mixture, and methanol was removed under reducedpressure. Impurities were extracted into 90% ethyl acetate-hexanes, theaqueous layer was then acidified by adding solid citric acid until thepH reached 2-3. The product was extracted into 90% ethylacetate-hexanes. This organic layer was dried (Na₂SO₄) and filtered.Removal of the solvents under reduced pressure afforded a quantitativeyield of the product b.

Example 11 N-Boc-fluoro-L-alanine

A mixture of unprotected amino acid a (775 mg, 7.24 mmol) and sodiumcarbonate (1.69 g, 16.0 mmol) was dissolved in a 1:1 solution ofdeionized water and THF (15 mL each). To this mixture was addedBOC-anhydride b (1.73 g, 7.96 mmol). The mixture was stirred at roomtemperature overnight, and THF was removed under reduced pressure. Themixture was then acidified to pH 2-3 with saturated aqueous citric acid,and product was extracted into 10% ethyl acetate-dichloromethane. Theorganic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure to afford clean BOC-protected amino acid c (1.40 g, 6.7mmol, 93%) to be used without further purification.

Example 12 Compound 1

In a 100 mL round-bottomed flask, compound a (1.62 g, 4.97 mmol) and2-amino-5-bromopyridine b (1.0 g, 6.00 mmol) were mixed together inethanol (50 mL) and stirred at 80° C. for 48 h. The mixture was thencooled down and concentrated. The residue was adsorbed on silica gel andpurified by flash chromatography (100% DCM to 10% Methanol/DCM) toafford 881 mg (35.4%) of compound c as an orange oil. LCMS: M/Z=401.

Into a 25 mL round-bottomed flask, compound c (150 mg, 0.37 mmol),phenylboronic acid (68 mg, 0.56 mmol),tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol) andpotassium carbonate (78 mg, 0.56 mmol) were mixed together in DMF (2.0mL). The mixture was stirred at 100° C. under nitrogen atmosphere for 18h. The mixture was then cooled down, diluted with ethyl acetate (30 mL)and washed with water (50 mL). The aqueous phase was extracted withethyl acetate (30 mL). The combined organic phases were washed withsaturated aqueous NaHCO₃ (50 mL) and brine (50 mL), dried with MgSO₄,filtered and concentrated. The residue was adsorbed on silica gel andpurified by flash chromatography (30% ethyl acetate/hexane to 100% ethylacetate) to afford 126 mg (84%) of compound d as a pale yellow oil.

LCMS: M/Z=398.

In a 50 mL round-bottomed flask, compound d (120 mg, 0.30 mmol) wasdissolved in ethanol (10 mL) and 10% palladium on carbon (24 mg) wasadded. The mixture was stirred at room temperature under a hydrogenatmosphere for 48 h. The mixture was then filtered over celite andwashed with ethanol. The filtrate was concentrated to afford 78 mg (98%)of compound e as a pale yellow oil. LCSM: M/Z=264.

In a 10 mL round-bottomed flask, compound e (78 mg, 0.30 mmol), compoundf (120 mg, 0.36 mmol), N,N-diisopropylcarbodiimide (0.074 mL, 0.47 mmol)and 1-hydroxy-7-azabenzotriazole (64 mg, 0.47 mmol) were mixed togetherin dichloromethane (2.0 mL). The mixture was stirred at room temperatureunder a nitrogen atmosphere for 5 h. The mixture was then concentratedon silica gel and purified by flash chromatography (100% DCM to 7%MeOH/DCM) to afford 182 mg (50%) of compound g as pale yellow oil. LCMS:M/Z=590.

In a 25 mL round-bottomed flask, compound g (192 mg, 0.33 mmol) wasdissolved in a solution of 4N hydrogen chloride in dioxane (4 mL, 30mmol). The mixture was stirred at room temperature for 1 h. The mixturewas then concentrated and the residue was purified by HPLC to afford13.3 mg (8.3%) of compound l as a white solid. LCMS: M/Z=490.

Example 13 (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate

Alpha bromo ketone was prepared according to the general procedure ofBures and Kulhanek (Tetrahedron: Assymetry (2005) 16(7):1347-1354.)

A solution of Diazald (4.9991 g, 23.3 mmol), sodium sulfate (20.14 g),and diethyl ether (15 mL) was stirred for 15 min. The resulting mixturewas then filtered and added dropwise to a solution of potassiumhydroxide (5.0050 g) in water (8 mL) and ethanol (10 mL) at 65° C. in amini Diazald apparatus and distilled until the reaction mixture was paleyellow. The distilled diazomethane solution was stored over sodiumhydroxide pellets at 4° C.

To a solution of Cbz-Pro-OH (2.9986 g, 12.0 mmol) in dry tetrahydrofuran(40 mL) and dry diethyl ether (40 mL) was added triethylamine (1.7 mL,12.2 mmol). The solution was cooled to −25° C. and isobutylchloroformate (1.6 mL, 12.3 mmol) was added dropwise. The resultingsolution was stirred at −25° C. for 30 min before warming to −10° C. Thediazomethane solution was added to the reaction mixture. The sample wasstirred at −10° C. for 1 hour. The reaction mixture was concentrated toone half of its original volume and washed once with saturated sodiumbicarbonate (50 mL). The organic layer was dried over magnesium sulfateand filtered. The crude material was adsorbed onto silica gel andpurified by flash chromatography (40 g SiO₂, 0-50% ethyl acetate inhexanes) to give the diazoketone (2.29 g, 8.3 mmol, 69%).

The diazoketone (1.72 g, 6.3 mmol) was dissolved in acetic acid (40 mL)and cooled to 0° C. 48% HBr (1.1 mL, 9.7 mmol) was added dropwise to thesolution. The reaction mixture was warmed to room temperature andstirred for 1 hour. The sample was poured into ice and added sodiumbicarbonate (5 g). The solution was extracted with dichloromethane(3×100 mL). The organic extracts were washed with saturated sodiumbicarbonate (3×100 mL). The dichloromethane extracts were dried overmagnesium sulfate, filtered, and concentrated to give the α-bromoketone(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (1.771 g, 5.4mmol, 86%). The α-bromoketone was unstable at room temperature as wellas 4° C. when stored neat.

Example 14 (S)-benzyl2-(8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (1.771 g, 5.4mmol), 2-amino-3-bromo-pyridine (0.9412 g, 5.4 mmol), and ethanol (20mL) were combined under nitrogen. The reaction mixture was heated to 78°C. and stirred overnight. The sample was concentrated and saturatedsodium bicarbonate (50 mL) was added. The mixture was extracted withethyl acetate (3×50 mL). The ethyl acetate extracts were dried overmagnesium sulfate and filtered. The crude material was adsorbed ontosilica gel and purified by flash chromatography (40 g SiO₂, 0-100% ethylacetate in hexanes) to give(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.869 g, 8.3 mmol, 2.2 mmol, 40%).

To a 2-5 ml microwave vial with a stirbar was added(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.258 g, 0.644 mmol), phenylboronic acid (0.1026 g, 0.8415 mmol) andpotassium carbonate (0.142 g, 1.03 mmol). The reaction vial wasevacuated and purged with N₂ three times.Tetrakis(triphenylphosphine)-palladium(0) (0.0395 g, 0.0342 mmol) wasthen added and the vial evacuated and purged with N₂ five times. 3 ml ofDMF was added, then 1 ml of deoxygenated H₂O, and the vial wasmicrowaved at 130° C. for 40 min. LC/MS showed no starting materialremaining, so the reaction was poured into 200 ml H₂O and extracted withethyl acetate (3×50 ml) and the combined extracts were dried with MgSO₄,filtered and concentrated under reduced pressure. The crude material wasdissolved in dichloromethane and applied to a 12 g column which had beenequilibrated in hexanes. The material was flashed using a gradient of 0%to 50% ethyl acetate in hexanes. The product containing fractions werecombined and evaporated under reduced pressure to give the desiredimidazopyridine (S)-benzyl2-(8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate.

Example 15 (2S)-benzyl2-(8-o-tolylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following procedures of example 14,(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.250 g, 0.62 mmol), o-tolyl boronic acid (0.1101 g, 0.81 mmol),potassium carbonate (0.1292 g, 0.93 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0360 g, 0.03 mmol) werereacted to give crude (2S)-benzyl2-(8-o-tolylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate. Thecrude material was adsorbed onto silica gel and purified by flashchromatography (4 g SiO₂, 0-70% ethyl acetate in hexanes) to give thefinal product (0.247 g, 0.60 mmol, 74%).

Example 16(2S)-benzyl-2-(8-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following procedures of example 14,(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.250 g, 0.62 mmol), 2-trifluoromethylphenyl boronic acid (0.1538 g,0.81 mmol), potassium carbonate (0.1292 g, 0.93 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0360 g, 0.03 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-100% ethyl acetate in hexanes) to give(2S)-benzyl-2-(8-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.264 g, 0.57 mmol, 70%).

Example 17(2S)-benzyl-2-(8-(2-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following the procedures of example 14,(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.250 g, 0.62 mmol), 2-methoxyphenyl boronic acid (0.1231 g, 0.81mmol), potassium carbonate (0.1292 g, 0.93 mmol), andtetrakis(triphenylphosphine)-palladium(0) (0.0360 g, 0.03 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-100% ethyl acetate in hexanes) to give(2S)-benzyl-2-(8-(2-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.269 g, 0.63 mmol, 78%).

Example 18(2S)-benzyl-2-(8-(naphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following the procedures of example 14,(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.250 g, 0.62 mmol), 1-napthyl boronic acid (0.1405 g, 0.82 mmol),potassium carbonate (0.1340 g, 0.97 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0430 g, 0.04 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-50% ethyl acetate in hexanes) to give(2S)-benzyl2-(8-(naphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.183 g, 0.41 mmol, 66%).

Example 19(2S)-benzyl-2-(8-(2-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following the procedures of example 14,(S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.2489 g, 0.62 mmol), 2-fluorophenyl boronic acid (0.1217 g, 0.87mmol), potassium carbonate (0.1449 g, 1.05 mmol), andtetrakis(triphenylphosphine)-palladium(0) (0.0532 g, 0.05 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-60% ethyl acetate in hexanes) to give(2S)-benzyl2-(8-(2-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.62 mmol, 100%).

Example 20(S)-benzyl-2-(6-methyl-8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following the procedures of example 14,(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.295 g, 0.90mmol) and 2-amino-3-bromo-5-methylpyridine (0.1765 g, 0.94 mmol),produced the crude material which was adsorbed onto silica gel andpurified by flash chromatography (12 g SiO₂, 0-50% ethyl acetate inhexanes) to give(S)-benzyl-2-(8-bromo-6-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.165 g, 0.40 mmol, 44%).

(S)-benzyl-2-(8-bromo-6-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.165 g, 0.40 mmol), phenyl boronic acid (0.0740 g, 0.61 mmol),potassium carbonate (0.1449 g, 0.65 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0351 g, 0.03 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-50% ethyl acetate in hexanes) to give(S)-benzyl-2-(6-methyl-8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.40 mmol, 100%).

Example 21(S)-benzyl-2-(7-methyl-8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

Following the procedures of example 14,(S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.400 g, 1.23mmol) and 2-amino-3-bromo-4-methylpyridine (0.2344 g, 1.25 mmol),produced the crude material which was adsorbed onto silica gel andpurified by flash chromatography (12 g SiO₂, 0-50% ethyl acetate inhexanes) to give(S)-benzyl-2-(8-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.239 g, 0.58 mmol, 47%).

(S)-benzyl2-(8-bromo-7-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.239 g, 0.58 mmol), phenyl boronic acid (0.0936 g, 0.77 mmol),potassium carbonate (0.1496 g, 1.08 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.0534 g, 0.05 mmol) producedthe crude material which was adsorbed onto silica gel and purified byflash chromatography (4 g SiO₂, 0-60% ethyl acetate in hexanes) to give(S)-benzyl2-(7-methyl-8-phenylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate(0.58 mmol, 100%).

Example 22 IAP Inhibition Assays

In the following experiments was used a chimeric BIR domain referred toas MLXBIR3SG in which 11 of 110 residues correspond to those found inXIAP-BIR3, while the remainder correspond to ML-IAP-BIR. The chimericprotein MLXBIR3SG was shown to bind and inhibit caspase-9 significantlybetter than either of the native BIR domains, but bound Smac-basedpeptides and mature Smac with affinities similar to those of nativeML-IAP-BIR. The improved caspase-9 inhibition of the chimeric BIR domainMLXBIR3SG has been correlated with increased inhibition ofdoxorubicin-induced apoptosis when transfected into MCF7 cells.MLXBIR3SG sequence:

(SEQ ID NO.: 1) MGSSHHHHHHSSGLVPRGSHMLETEEEEEEGAGATLSRGPAFPGMGSEELRLASFYDWPLTAEVPPELLAAAGFFHTGHQDKVRCFFCYGGLQSWKRGDDPWTEHAKWFPGCQFLLRSKGQEYINNIHLTHSLTR-FRET Peptide Binding Assay

Time-Resolved Fluorescence Resonance Energy Transfer competitionexperiments are performed on the Wallac Victor2 Multilabeled CounterReader (Perkin Elmer Life and Analytical Sciences, Inc.) according tothe procedures of Kolb et al (Journal of Biomolecular Screening, 1996,1(4):203). A reagent cocktail containing 300 nM his-tagged MLXBIR3SG;200 nM biotinylated SMAC peptide (AVPI); 5 μg/mL anti-hisallophycocyanin (XL665) (CISBio International); and 200 ng/mLstreptavidin-europium (Perkin Elmer) was prepared in reagent buffer (50mM Tris [pH 7.2], 120 mM NaCl, 0.1% bovine globulins, 5 mM DTT and 0.05%octylglucoside). (Alternatively, this cocktail can be made usingeuropium-labeled anti-His (Perkin Elmer) andstreptavidin-allophycocyanin (Perkin Elmer) at concentrations of 6.5 nMand 25 nM, respectively). The reagent cocktail is incubated at roomtemperature for 30 minutes. After incubation, the cocktail is added to1:3 serial dilutions of an antagonist compound (starting concentrationof 50 μM) in 384-well black FIA plates (Greiner Bio-One, Inc.). After a90 minute incubation at room temperature, the fluorescence is read withfilters for the excitation of europium (340 nm) and for the emissionwavelengths of europium (615 nm) and a allophycocyanin (665 nm).Antagonist data is calculated as a ratio of the emission signal ofallophycocyanin at 665 nm to that of the emission of europium at 615 nm(these ratios are multiplied by a factor of 10,000 for ease of datamanipulation). The resulting values are plotted as a function ofantagonist concentration and fit to a 4-parameter equation usingKaleidograph software (Synergy Software, Reading, Pa.). Indications ofantagonist potency are determined from the IC₅₀ values.

Fluorescence Polarization Peptide Binding Assay

Polarization experiments were performed on an Analyst HT 96-384(Molecular Devices Corp.) according to the procedure of Keating, S. M.,Marsters, J, Beresini, M., Ladner, C., Zioncheck, K., Clark, K.,Arellano, F., and Bodary., S. (2000) in Proceedings of SPIE: In VitroDiagnostic Instrumentation (Cohn, G. E., Ed.) pp 128-137, Bellingham,Wash. Samples for fluorescence polarization affinity measurements wereprepared by addition of 1:2 serial dilutions starting at a finalconcentration of 5 μM of MLXBIR3SG in polarization buffer (50 mM Tris[pH 7.2], 120 mM NaCl, 1% bovine globulins 5 mM DTT and 0.05%octylglucoside) to 5-carboxyflourescein-conjugated AVPdi-Phe-NH₂(AVP-diPhe-FAM) at 5 nM final concentration.

The reactions were read after an incubation time of 10 minutes at roomtemperature with standard cut-off filters for the fluoresceinfluorophore (λ_(ex)=485 nm; λ_(em)=530 nm) in 96-well black HE96 plates(Molecular Devices Corp.). Fluorescence values were plotted as afunction of the protein concentration, and the IC50s were obtained byfitting the data to a 4-parameter equation using Kaleidograph software(Synergy software, Reading, Pa.). Competition experiments were performedby addition of the MLXBIR3SG at 30 nM to wells containing 5 nM of theAVP-diPhe-FAM probe as well as 1:3 serial dilutions of antagonistcompounds starting at a concentration of 300 μM in the polarizationbuffer. Samples were read after a 10-minute incubation. Fluorescencepolarization values were plotted as a function of the antagonistconcentration, and the IC₅₀ values were obtained by fitting the data toa 4-parameter equation using Kaleidograph software (Synergy software,Reading, Pa.). Inhibition constants (K_(i)) for the antagonists weredetermined from the IC₅₀ values. Compounds of the invention that weretested in this assay exhibited a Ki or less than 50 μM. For example,compound 7 had a Ki of 18.917, compound 20 had a Ki of 1.8312, compound1 had an Ki of 0.0891 and compound 8 had a Ki of 2.3067.

1. A compound of formula (I)

wherein X₁ and X₂ are each independently O or S; Y is a bond,(CR₇R₇)_(m), O or S; Z is H, alkyl, a carbocycle or a heterocycle;wherein said alkyl, carbocycle and heterocycle is optionally substitutedwith one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo,carboxyl, acyl, optionally substituted alkyl, amino, cyano, nitro,amidino, guanidino an optionally substituted carbocycle or an optionallysubstituted heterocycle; and wherein one or more CH₂ or CH groups of analkyl is optionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—,—C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—, —NR₈—C(O)—NR₈—,—NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)—; Q is H, halogen,hydroxyl, carboxyl, amino, nitro, cyano, alkyl, a carbocycle or aheterocycle; wherein said alkyl, carbocycle and heterocycle isoptionally substituted with one or more hydroxyl, alkoxy, acyl, halogen,mercapto, oxo, carboxyl, acyl, optionally substituted alkyl, amino,cyano, nitro, amidino, guanidino an optionally substituted carbocycle oran optionally substituted heterocycle; and wherein one or more CH₂ or CHgroups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O)₂,—N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—,—NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)—; R₁is H, OH or alkyl; or R₁ and R₂ together form a 5-8 member heterocycle;R₂ is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle orheterocyclylalkyl each optionally substituted with halogen, hydroxyl,oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, acyl, alkoxy,alkylthio, sulfonyl, amino and nitro, wherein said alkyl, acyl, alkoxy,alkylthio and sulfonyl are optionally substituted with hydroxy,mercapto, halogen, amino, alkoxy, hydroxyalkoxy and alkoxyalkoxy; R₃ isH or alkyl optionally substituted with halogen or hydroxyl; or R₃ and R₄together form a 3-6 heterocycle; R₃′ is H, or R₃ and R₃′ together form a3-6 carbocycle; R₄ and R₄′ are independently H, hydroxyl, amino, alkyl,carbocycle, carbocycloalkyl, carbocycloalkyloxy,carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl,heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl,carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl,heterocycle, heterocycloalkyl, heterocycloalkyloxy andheterocycloalkyloxycarbonyl is optionally substituted with halogen,hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino and nitro; orR₄ and R₄′ together form a heterocycle; R₅ is H or alkyl; R₆, and R₆′are each independently H, alkyl, aryl or aralkyl; R₇ is H, cyano,hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl,a carbocycle, a heterocycle or -U-V; wherein U is —O—, —S—, —S(O)—,S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂-—,—NR₈—C(O)—NR₈—, C(NH)—NR₈—, —NR₈—C(NH)—, —C(O)—O— or —O—C(O)— and V isalkyl, a carbocycle or a heterocycle; and wherein one or more CH₂ or CHgroups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, S(O)₂,—N(R₈)—, —C(O)—, —C(O)—NR₈—, —NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂—,—NR₈—C(O)—NR₈—, —C(O)—O— or —O—C(O)—; and an alkyl, carbocycle andheterocycle is optionally substituted with hydroxyl, alkoxy, acyl,halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino,cyano nitro, amidino, guanidino an optionally substituted carbocycle oran optionally substituted heterocycle; R₈ is H, alkyl, a carbocycle or aheterocycle wherein one or more CH₂ or CH groups of said alkyl isoptionally replaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈), or —C(O)—; andsaid alkyl, carbocycle and heterocycle is optionally substituted withhydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl,halo-substituted alkyl, amino, cyano nitro, amidino, guanidino anoptionally substituted carbocycle or an optionally substitutedheterocycle; and m is 0 to
 4. 2. The compound of claim 1, wherein Z isH, halogen or alkyl.
 3. The compound of claim 1, wherein Y is CH₂. 4.The compound of claim 1, wherein Q is a carbocycle or heterocycleoptionally substituted with alkyl, a carbocycle or a heterocycle;wherein any alkyl, carbocycle or heterocycle is optionally substitutedwith halogen, amino, hydroxyl, mercapto, carboxyl, alkoxy, alkoxyalkoxy,hydroxyalkoxy, alkylthio, acyloxy, acyloxyalkoxy, alkylsulfonyl,alkylsulfonylalkyl, alkylsulfinyl, and alkylsulfinylalkyl; and whereinone or more CH₂ or CH groups of any foregoing alkyl is optionallyreplaced with —O—, —S—, —S(O)—, S(O)₂, —N(R₈)—, —C(O)—, —C(O)—NR₈—,—NR₈—C(O)—, —SO₂—NR₈—, —NR₈—SO₂-, —NR₈—C(O)—NR₈—, —NR₈—C(NH)—NR₈—,—NR₈—C(NH)—, —C(O)—O— or —O—C(O)—;
 5. The compound of claim 1, wherein Qis a carbocycle or heterocycle selected from the group consisting ofIIIa-IIIs:

wherein n is 1-4; T is O, S, NR₈ or CR₇R₇; and W is O, NR₈ or CR₇R₇. 6.The compound of claim 1, wherein R₁ is H.
 7. The compound of claim 1,wherein R₂ is alkyl, cycloalkyl or a heterocycle.
 8. The compound ofclaim 1, wherein R₂ is selected from the group consisting of t-butyl,isopropyl, cyclohexyl, tetrahydropyran-4-yl,N-methylsulfonylpiperidin-4-yl, tetrahydrothiopyran-4-yl,tetrahydrothiopyran-4-yl (in which the S is in oxidized form SO or SO₂),cyclohexan-4-one, 4-hydroxycyclohexane, 4-hydroxy-4-methylcyclohexane,1-methyl-tetrahydropyran-4-yl, 2-hydroxyprop-2-yl, but-2-yl,thiophen-3-yl, piperidin-4-yl, N-acetylpiperidin-4-yl,N-hydroxyethylpiperidin-4-yl, N-(2-hydroxyacetyl)piperidin-4-yl,N-(2-methoxyacetyl)piperidin-4-yl, pyridin-3-yl, phenyl and1-hydroxyeth-1-yl.
 9. The compound of claim 1, wherein R₃ is methyl. 10.The compound of claim 1, wherein R₄ is H or methyl, and R₄′ is H. 11.The compound of claim 1, wherein R₅ is H.
 12. The compound of claim 1,wherein R₆ and R₆′ are both H.
 13. The compound of claim 1, wherein X₁and X₂ are both O.
 14. The compound of claim 2, wherein R₁ is H; R₂ isisopropyl, t-butyl, cyclohexyl or pyran; R₃ is methyl; R₃, is H; R₄ ismethyl, R₄′ is H; R₅ is H; X₁ and X₂ are both O; and R₆ and R₆, are bothH.